This is an application for an NIDDK mentored career development award for John Wilkinson IV. Free or labile iron is a central mediator of oxidative stress. Ferritin, the primary cellular iron storage protein, is thought to buffer free iron flux and moderate the generation of oxygen free radicals. The role of ferritin in this critical process has been demonstrated in elegant cellular model systems, but has not been directly tested in vivo. To assess the function of ferritin in vivo, we have constructed conditional ferritin H transgenic mice in which ferritin H expression can be temporally controlled and targeted to specific organs. The ferritin H transgene contains a mutation in the iron responsive element that enables it to escape from translational control. We hypothesize that modulation of ferritin H regulates oxidative stress through its impact on cellular iron levels; thus, by regulating ferritin expression in vivo we can alter iron metabolism and the ability of iron to cause oxidative stress-induced cellular damage. To test this hypothesis we will conduct experiments according to the following aims: In Specific Aim One we will use the transgenic ferritin H model to understand the relationship between ferritin and iron metabolism. In Specific Aim Two we will use this model to assess the relationship between ferritin, accessible iron, and oxidative stress. In Specific Aim Three the model will be used to characterize the impact of ferritin on cellular oxidant defenses. Accomplishing these aims will increase our understanding of the role of ferritin in iron metabolism, will help define the scope of the influence ferritin can have on oxidant stress, and will establish an important model system for the study of diseases which involve oxidative stress such as atherosclerosis, cancer, diabetes, hematologic disorders, renal dysfunction, and neurodegeneration. The candidate's career development plan includes weekly meetings with his mentors, quarterly meetings with an advisory committee, attendance at several career development oriented workshops and seminars, training in the responsible conduct of science via an ethics course, and animal and radioactive safety training, and the development of collegial interactions through administration of a journal club which is topically pertinent to the studies conducted, as well as through presentation of his work at national meetings.